1. Field of the Invention
The present invention relates to a method for preparing swainsonine. The present invention also relates to novel intermediates useful for the production of swainsonine.
2. Discussion of the Background
The indolizidine alkaloid (-)-swainsonine (1) is of long standing interest due to its diverse biological activity. For the isolation from the fungus Rhizoctonia leguminicola, see:
(a) Guengerich, F. P.; DiMari, S. J.; Broquist, H. P. J. Am. Chem. Soc. 1973, 95, 2055.
(b) Schneider, M. J.; Ungemach, F. S.; Broquist, H. P.; Harris, T. M. Tetrahedron 1983, 39, 29-32.
For the isolation from the fungus Metarhizium anisopliae, see:
(c) Hino, M.; Nakayama, O.; Tsurumi, Y.; Adachi, K.; Shibata, T.; Terano, H.; Kohsaka, M.; Aoki, H.; Imanaka, H. J. Antibiot. 1985, 35, 926-935.
(d) Patrick, M. S.; Adlard, M. W.; Keshavarz, T. Biotechnol. Lett. 1995, 17, 433-438.
For the isolation from the legume Swainsona canescens, see:
(e) Colegate, S. M.; Dorling, P. R.; Huxtable, C. R. Aust. J. Chem. 1979, 32, 2257-64.
For the isolation from the locoweed Astragalus lentiginosus, see:
(f) Molyneux, R. J.; James, L. F. Science, 1982, 216, 190-191.
For the isolation from Weir vine, see:
(g) Molyneux, R. J.; McKenzie, R. A.; O'Sullivan, B. M.; Elbein, A. D. J. Nat. Prod. 1995, 58, 878-886.
For a review of the synthesis and biological activity of swainsonine and other glycosidase inhibitors, see: Nishimura, Y. In Studies in Natural Products Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1992; Vol. 10; pp 495-583.
(-)-Swainsonine may be considered an azasugar analog of mannose, and is indeed a potent inhibitor of many mannosidases including the glycoprotein processing enzyme mannosidase II (see: Elbein, A. D. Ann. Rev. Biochem 1987, 56, 497-534; Cenci Di Bello, I.; et al Biochem. J. 1989, 259, 855-861; Winchester, B., et al; Glycobiology, 1992, 2, 199-210; and Kaushal, G. P.; Elbein, A. D. Methods in Enzymology 1994, 230, 316-329). Swainsonine is the first glycoprotein-processing inhibitor to be selected for clinical testing as an anticancer drug (see: Goss, P. E.; Baker, M. A.; Carver, J. P.; Dennis, J. W. Clin. Cancer Res. 1995, 1, 935-944; and Das, P. C.; Roberts, J. D.; White, S. L.; Olden, K. Oncol. Res. 1995, 7, 425-433), but its high cost has hindered clinical trials. For example, Sigma Chemical Co. currently sells 1 mg of (-)-swainsonine isolated from Rhizoctonia leguminicola for ca. $100 USD (1995 catalog). Toronto Research Chemicals currently sells 1 mg of synthetic (-)-swainsonine for ca. $40. Apparently, there is still no cost-effective way to either isolate swainsonine from natural sources or to prepare it synthetically.
A great deal of effort has been expended on developing synthetic routes to swainsonine. See e.g.,
(a) Suami, T.; Tadano, K.; Iimura, Y. Chem. Lett. 1984, 513-516.
(b) Ali, M. H.; Hough, L.; Richardson, A. C. J. Chem. Soc., Chem. Commun. 1984, 447-448.
(c) Fleet, G. W. J.; Gough, M. J.; Smith, P. W. Tetrahedron Lett. 1984, 25, 1853-1856.
(d) Yasuda, N.; Tsutsumi, H.; Takaya, T. Chem. Lett. 1984, 1201-1204.
(e) Adams, C. E.; Walker, F. J.; Sharpless, K. B. J. Org. Chem. 1985, 50, 420-422.
(f) Suami, T.; Tadano, K. Iimura, Y. Carbohydr. Res. 1985, 136, 67-75.
(g) Ali, M. H.; Hough, L. Richardson, A. C. Carbohydr. Res. 1985, 136, 225-240.
(h) Setoi, H.; Takeno, H.; Hashimoto, M. J. Org. Chem. 1985, 50, 3948-3950.
(i) Ikota, N.; Hanaki, A. Chem. Pharm. Bull. 1987, 35, 2140-21433.
(j) Ikota, N.; Hanaki, A. Heterocycles 1987, 26, 2368.
(k) Bashyal, B. P.; Fleet, G. W. J.; Gough, M. J.; Smith, P. W. Tetrahedron 1987, 43, 3083.
(l) Dener, J. M.; Hart, D. J. Ramesh, S. J. Org. Chem. 1988, 53, 6022-6030.
(m) Carpenter, N. M.; Fleet, G. W. J.; diBello, I. C.; Winchester, B.; Fellows, L. E.; Nash, R. J. Tetrahedron Lett. 1989, 30, 7261-7264.
(n) Bennett, R. B., III; Choi, J.-R.; Montgomery, W. D.; Cha, J. K. J. Am. Chem. Soc., 1989, 111, 2580-2582.
(o) Pearson, W. H.; Lin, K.-C. Tetrahedron Lett., 1990, 31, 7571.
(p) Miller, S. A.; Chamberlin, A. R. J. Am. Chem. Soc., 1990, 112, 8100-8112.
(q) Ikota, N.; Hanaki, A. Chem. Pharm. Bull. 1990, 38, 2712.
(r) Fleet, G. W. J. U.S. Pat. No. 5,023,340, 1991.
(s) Naruse, M.; Aoyagi, S.; Kibayashi, C. J. Org. Chem., 1994, 59, 1358-1364.
(t) Hunt, J. A.; Roush, W. R. Tetrahedron Lett. 1995, 36, 501-504.
(u) Kang, S. H.; Kim, G. T. Tetrahedron Lett. 1995, 36, 5049-5052.
For a synthesis of the non-natural (+)-enantiomer of swainsonine, see:
(v) Oishi, T.; Iwakuma, T.; Hirama, M.; Ito, S. Synlett 1995, 404-406.
For formal syntheses, see:
(w) Gonzalez, F. B.; Barba, A. L.; Espina, M. R. Bull. Chem. Soc. Jpn. 1992, 65, 567-574.
(x) Honda, T.; Hoshi, M.; Kanai, K.; Tsubuki, M. J. Chem. Soc., Perkin Trans. 1 1994, 2091-2101.
(y) Angermann, J.; Homann, K.; Reissig, H.-U.; Zimmer, R. Synlett 1995, 1014-1016.
(z) Zhou, W.-S.; Xie, W.-G.; Lu, Z.-H.; Pan, X.-F. Tetrahedron Lett., 1995, 36, 1291-1294.
(aa) Zhou, W.-S.; Xie, W.-G.; Lu, Z.-H.; Pan, X.-F. J. Chem. Soc., Perkin Trans. 1 1995, 2599-2604.
However, there is still a need for a practical synthesis of this important alkaloid. Perhaps the most practical routes developed to date are those reported by the research groups of Fleet (see: Carpenter, N. M.; Fleet, G. W. J.; diBello, I. C.; Winchester, B.; Fellows, L. E.; Nash, R. J. Tetrahedron Lett. 1989, 30, 7261-7264; and Fleet, G. W. J. U.S. Pat. No. 5,023,340, 1991) and Cha (see: Bennett, R. B., III; Choi, J.-R.; Montgomery, W. D.; Cha, J. K. J. Am. Chem. Soc., 1989, 111, 2580-2582). In addition, a short synthetic route recently developed has not proven amenable to scale-up (Pearson, W. H.; Lin, K.-C. Tetrahedron Lett., 1990, 31, 7571).
Thus, there remains a need for a synthesis of (-)-swainsonine that is relatively short and efficient and uses simple reactions that allow good reproducibility and material throughput. There also remains a need for intermediates useful for the production of swainsonine.